Esophageal reflux occurs in physiological conditions, in particular in newborns, but when it overcomes the esofageal mucosa defence mechanisms, it may cause diseases such as GERD.
GERD is the more frequent gastric disease and it is due to gastric or enteric reflux in the esophagus, leading to reflux esophagitis, a very common disease with typical esophageal mucosa inflammation and lesions (erosions and small ulcers) due to the gastric or enteric juice reflux in the esophagus.
In GERD the reflux lead to symptoms similar to esophagitis, but not to lesions.
Normally a pressure gradient between esophagus and stomach inhibits the back flow of gastric contents in the esophagus.
The anatomical structure mainly involved in maintaining the pressure gradient is the LES (Lower Esophageal Sphincter), a muscular ring at the esophagus and stomach joint, which relaxes during swallowing.
In physiological conditions, when gastric (acid) substances reflux in the esophagus, the esophageal peristalsis (esophageal muscle contractions) push them back to the stomach, and their acid residues are buffered and neutralized by the saliva swallowed.
GERD is characterized by similarity between pressures in the esophagus and in the stomach, respectively. This could be due to:                lowered or absent LES tone;        LES relaxation in the absence of swallowing;        Reduced elimination of acidic material caused by abnormal esophageal peristalsis;                    Abnormal function of cardias, the valve between stomach and esophagus that inhibits, in physiological conditions, the reflux of gastric contents in the esophagus.                        
The imperfect cardias closure may be due to different causes, such as obesity, smoke, multiple pregnancies, hard physical efforts, pharmacological treatments or hiatus hernia.
The serious types of reflux esophagitis may lead to esophagus stricture (stenosis) caused by esophagitis healing at the recovery, or to precancerous lesions (“Barrett's esophagus”, esofageal adenocarcinoma) that produce an esophageal mucosa metaplasia, taking typical appearance of gastric or duodenal mucosa. In some patients other factors are involved such as lowered saliva secretion, exaggerated acidic secretion, delayed gastric emptying, biliary salts or pancreatic enzymes reflux.
These diseases are characterized by heartburn (hard retrosternal burning), burps and food or acid regurgitation in the mouth. These symptoms can be associated with others affecting the respiratory system (chronic cough, asthma, hoarseness, chronic laryngitis) teeth (enamel losing) or ear (otalgia).
GERD and reflux esophagitis, in case of acidic reflux, are currently treated with 1) proton pump inhibitors (PPI, e.g. omeprazole, lansoprazole) H2 receptor antagonists (e.g. cimetidine and ranitidine), that reduce the acidic gastric secretion and consequently the reflux; 2) prokinetic agents (e.g. metoclopramide, domperidone, laevosulpiride), that increase the cardias valve tone and improve the gastric emptying; 3) antacid agents (e.g. bicarbonate, magnesium and aluminium hydroxide) and cytoprotective agents (e.g. sucralfate), that reduce gastric acidity and protect esophageal mucosa.
Only few drugs are useful in case of non-acid (enteric) regurgitation.
Dietary, postural and behavioural rules that help to reduce or to prevent symptoms are associated with the pharmacological therapy. For example, it is recommended to avoid alcohol, abundant meals or fatty, spicy or irritant foods (mint, chocolate, coffee, tea), and to sleep with a pillow raised by some centimetres.
The pharmacological therapy does not affect the disease's cause (ill-functioning cardias) and it must be taken for very long periods (even the entire life) as almost all patients suffer from disease recurrence once the therapy is interrupted.
The dysfunctional cardias valve closure may be corrected with surgical therapy: this leads to perfect recovery from the disease, but if it is not well performed it may determine the appearance of new symptoms. Moreover, the surgical treatment is recommended for young subjects, in excellent general condition and who are in need of continuous high dose therapy. Recently Dr. Higa proposed a new surgical method able to reduce GERD, but this new technique is not very widespread.
There are not clear indications for preferring one specific pharmacological therapy for the treatment of GERD or reflux esophagitis: physicians choose in general on the basis of their personal experience. Consequently, the choice of the therapy is very personal and not objective and it is possible that a physician has to try more than one pharmacological therapy prior to find the therapy best fitting the patient's physiology.
For patients with mild or occasional symptoms antacid agents, prokinetic agents, alginates and, in the most serious cases, H2 antagonists (anti H2) and proton pump inhibitors (PPI) are recommended.
Step up clinical protocols—where less effective drugs are gradually joined to or replaced by more effective actives, on the basis of symptomatology—and step down clinical protocols—where the therapy begins with highly effective actives such as proton pump inhibitors and continues with less effective actives—are provided for (Bytzer P., Goals of therapy and guidelines for treatment success in symptomatic gastroesophageal reflux disease patients, Am. J. Gastroenterol. 2003; 98(3) Suppl: S31-S39).
PPIs are much effective actives, but their prolonged use (which is needed in reflux esophagitis therapy) revealed serious side effects related to the long-term therapy with this class of actives such as increased risk of hip fracture as a result of calcium erratic absorption due to induction of hypochlorhidya (Yang et al., Long term proton pomp inhibitor therapy and risk of hip fracture, JAMA 2006, 296(94): 2947-2953), muscle diseases as well as polymyositis and rabdomiolisis (Clark et al., Myopathy including polymyositis: a likely class adverse effect of proton pump inhibitors?, Eur. J. Clin. Pharmacol., 2006 June, 62(6): 473-479).
Various PPI's side effects were reported from drug control data generated in Spain from the 1 Jan. to the 31 Dec. 2004 by Salquiero et al. (Salquiero et al., Safety profile of proton pump inhibitors according to the spontaneous reports of suspected adverse reactions, Int. J. Clin. Pharmacol. Ther., 2006 November, 44 (11): 548-556).
Alginates, which have a physical mechanism of action (gelling and foaming at the acidic gastric pH, in presence of HCO3−) are safer than PPIs, but are not useful in the treatment of non-acid esophageal reflux (Zentlin et al., An evaluation of the antireflux properties of sodium alginate by means of combined multichannel intraluminal impedance and pH-metry, Aliment Pharmacol Ther. 2005; 21: 29-34).
On the basis of the aforesaid and of the fabt that diseases such as GERD, reflux esophagitis and related diseases (dyspepsia, esophagitis, esophageal tumour, gastrointestinal disorders, chronic pharyngitis, Barrett's esophagus, esofageal adenocarcinoma, GERD-related pulmonary dysfunctions) are increasing, it is highly desirable to find a safe and effective treatment for the prevention and therapy of such diseases, avoiding the patient to undergo different treatments at the same time to obtain an effective therapeutic result.